T h e r a p e u t i c C o n t ro v e r s i e s i n Spondyloarthritis

Nonsteroidal Anti-Inflammatory Drugs

Denis Poddubnyy,
KEYWORDS  Spondyloarthritis  Ankylosing spondylitis  ASAS  Nonsteroidal anti-inflammatory drugs  Therapy KEY POINTS
 Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a first-line therapy in axial spondyloarthritis, including ankylosing spondylitis.  NSAIDs are highly effective in reduction of spondyloarthritis symptoms, including pain and stiffness.  NSAIDs also reduce activity of systemic inflammation and might have a (small) impact on the activity of local inflammatory lesions in the sacroiliac joints and the spine.  NSAIDs are able to reduce progression of structural damage in the spine if administered continuously, especially in patients who already have signs of structural damage (syndesmophytes) and elevated C-reactive protein and/or erythrocyte sedimentation rate.  Cardiovascular, gastrointestinal, renal, and hepatic risks should be taken into account if an NSAID is administered, especially if a long-term and continuous treatment is anticipated.
MD
a,

*, Dsire van der Heijde,

MD

INTRODUCTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered a first-line therapy in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS).1 Beyond NSAIDs, only tumor necrosis factor a (TNF-a) blockers are currently available and effective for treating axial signs and symptoms of patients with active axSpA.1,2 In contrast to rheumatoid arthritis, for example, disease-modifying antirheumatic drugs and corticosteroids play only a minor role in the management of axSpA, and only in the case of peripheral joint involvement.3,4 In the joint ASAS (Assessment of SpondyloArthritis international Society) and EULAR (European League Against Rheumatism) recommendations for the management of axSpA, continuous treatment with NSAIDs
sire e Disclosures: Denis Poddubnyy has received consultancy and speaking fees from Merck; De van der Heijde has received consultancy fees from Merck and Pfizer. a Universita tsmediRheumatology, Medical Department I, Campus Benjamin Franklin, Charite zin Berlin, Hindenburgdamm 30, Berlin 12203, Germany; b Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands * Corresponding author. E-mail address: denis.poddubnyy@charite.de Rheum Dis Clin N Am 38 (2012) 601611 http://dx.doi.org/10.1016/j.rdc.2012.08.005 rheumatic.theclinics.com 0889-857X/12/$ see front matter 2012 Elsevier Inc. All rights reserved.

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is preferred for patients with persistently active symptomatic disease.1 Continuous treatment with NSAIDs, however, raises safety issues. In a survey on the application of the ASAS/EULAR recommendations, 38% of European rheumatologists mentioned safety concerns as the main barrier for not using NSAIDs more consistently in patients with AS.5 This article discusses the current role of NSAIDs in axSpA treatment, including the risks and benefits of NSAID use and current trends for more individualized treatment strategies.
CLINICAL EFFICACY OF NSAIDS

So far, clinical trials with NSAIDs have only been performed in patients with established AS. However, based mainly on clinical experience, NSAIDs can be expected also to be highly effective in patients with nonradiographic axSpA (nr-axSpA), or those with axSpA who did not develop (yet) radiographic sacroiliitis. Thus, patients with nraxSpA should be treated with NSAIDs similarly to those with AS.6 Furthermore, NSAIDs also play an important role in the management of patients with predominant peripheral spondyloarthritis,1,7 who show only a limited response to conventional disease-modifying antirheumatic drugs.1 High clinical efficacy of NSAIDs for treating axial signs and symptoms of active axSpA/ AS was shown (against placebo and an active comparator) in several clinical trials with nonselective cyclooxygenase (COX) inhibitors and selective COX-2 antagonists.811 All NSAIDs, independently from their COX selectivity, are nearly equally effective in their therapeutic doses for reducing pain and stiffness in axSpA/AS. Nonetheless, great individual variation exists in response to and tolerability of NSAIDs. In general, trying at least one NSAID, but frequently several others, is worthwhile in case one is found to be ineffective. This sampling is also frequently performed in clinical practice: more than 20% of 1080 patients with AS who participated in a survey on NSAID use in Germany reported that they used at least 2 different NSAIDs (5% used !3 NSAIDs) within the past year.12 Good or very good improvement of AS symptoms is usually reported by 60% to 80% of patients treated with NSAIDs.7,8,11 In contrast, this level of response is only reported by approximately 15% of patients with chronic low back pain from noninflammatory causes.7 Furthermore, a good response to NSAID treatment is also used as a diagnostic approach to differentiate chronic back pain of inflammatory origin from other causes.7 Moreover, good pain control is necessary to perform physiotherapy effectively. Many clinical trials showed that reduction of pain and stiffness during NSAID therapy was associated with improvement of functional status in patients with AS measured using the Bath Ankylosing Spondylitis Functional Index.8,11,13 Up to 35% of active patients with AS treated with a full dose of an NSAID can fulfill even the ASAS criteria for partial remission.8,14 In a survey performed in Germany, almost 20% of the patients with AS reported complete pain control with NSAIDs, and another 60% of the patients reported a reduction in pain level from one-quarter to one-half.12 In most cases, NSAIDs reduce pain and stiffness rapidly, and a full effect can normally be observed after 48 to 72 hours. In some cases, a longer treatment period (up to 2 weeks) is necessary to achieve the complete anti-inflammatory and analgesic effect of an NSAID.8 However, if a response is not experienced within 2 weeks, it is unlikely to occur with continued treatment. To judge the therapeutic effect of an NSAID in a patient with axSpA/AS, a full therapeutic (inflammatory) dose is usually required. The dose and the intake frequency could be, however, adjusted based on the patients symptom intensity. In some patients with AS, a moderate dose might be sufficient for long-term treatment,

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whereas in others the highest tolerated dose might be necessary to achieve an optimal effect. On the group level, a higher efficacy could be demonstrated in patients treated with a higher dose of celecoxib (400 vs 200 mg/d),11 etoricoxib (120 vs 90 mg/d),8 or meloxicam (22.5 vs 15 mg/d)9 compared with a lower dose. Recently, the ASAS developed a recommendation for collecting, analyzing, and reporting NSAID intake in clinical trials and/or epidemiologic studies in axSpA.15 An index of NSAID intake was proposed, taking both dose and duration into account (Box 1). This index includes an NSAID equivalent score, which represents a standardized dose of an NSAID taken. Daily diclofenac dose of 150 mg (maximal recommended dose for treatment of arthritis) was accepted by consensus as a reference value, with the equivalent score of 100.15 Equivalent doses of other widely used NSAIDs are presented in Table 1. Daily doses of NSAIDs presented in table can be considered as full therapeutic doses for treatment of axSpA/AS.
INFLUENCE OF NSAIDS ON LOCAL AND SYSTEMIC INFLAMMATION IN axSpA

The high clinical efficacy of NSAIDs in axSpA indicates that their anti-inflammatory properties are more relevant for reducing pain and stiffness in this disease than their analgesic capacity only. However, the data indicating effective control of systemic and local inflammation with NSAIDs are limited. C-reactive protein (CRP) is a sensitive marker of systemic inflammation, and an elevated level of CRP could be found in approximately 50% of the patients with axSpA.16 Elevated serum CRP level was found recently to be an independent predictor of radiographic sacroiliitis progression (including progression from nraxSpA to AS)17 and of progression of structural damage in the spine.18 NSAIDs are able to decrease CRP serum level significantly already after 12 weeks of treatment, as shown in 2 recent studies in AS.10,11 Even more clinically appealing might be a reduction of local inflammation in the sacroiliac joints and spine. However, until now no solid data showed whether NSAIDs influence active inflammation in the axial skeleton as detected on MRI. Fig. 1 represents a case of near-complete resolution of active sacroiliitis after 2 weeks of treatment with a full dose of an NSAID for active axSpA. In the study by Jarrett and colleagues,19 22 patients who were eligible for the biologic therapy (ie, who did not respond to previous therapy with NSAIDs) were treated with 90 mg of etoricoxib for 6 weeks. Not surprisingly, this group of patients also showed no substantial improvement on MRI; only 13 of 60 active inflammatory lesions in the axial skeleton improved, whereas 5 lesions worsened or appeared during treatment.
Box 1 Formula for calculating the ASAS index of NSAID intake Index of NSAID intake 5 NSAID equivalent score Days of intake during period of interest Days per week Period of interest in days

Example: patient took diclofenac, 75 mg every day over the last 4 weeks that was also a period of interest. Index of NSAID intake 5 50 (equivalent score for 75 mg of diclofenac every day) 28 (4 weeks of intake) 7/7 (the NSAID was taken daily)/28 (period of interest) 5 50. Data from Dougados M, Simon P, Braun J, et al. ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis. Ann Rheum Dis 2011;70(2):24951.

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Table 1 Daily doses of NSAIDs equivalent to diclofenac 150 mg/d (NSAID equivalent score 5 100) Dose Therapeutically Equivalent to 150 mg of Diclofenac (Full Therapeutic Dose) in AS (mg) 200 400 600 90 200 2400 150 200 15 1000 200 400 20 20

NSAID Aceclofenaca Celecoxib Etodolac Etoricoxiba Flurbiprofen Ibuprofen Indomethacin Ketoprofen Meloxicam Naproxen Nimesulideb Phenylbutazonec Piroxicam Tenoxicama
a b

Currently not available in the United States. Not available in the United States, limited available in the European Union for short-term (up to 2 weeks) treatment of acute pain and primary dysmenorrhoea. c Not available in the United States, limited available in the European Union for short-term (up to 1 week) treatment. Data from Dougados M, Simon P, Braun J, et al. ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiologic studies in axial spondyloarthritis. Ann Rheum Dis 2011;70(2):24951.

Important data concerning the influence of NSAIDs on active inflammation were obtained in the recent infliximab as first line therapy in patients with early active axial spondyloarthritis trial (INFAST). In this study, patients with very early axSpA (symptom duration not longer than 3 years) were randomized to either naproxen plus infliximab or naproxen alone. Combination therapy with a TNF-a blocker and an NSAID was clearly superior to an NSAID alone; partial remission after 28 weeks of treatment was achieved in 62% of the patients in the combination arm, but was also observed in

Fig. 1. MRI of sacroiliac joints in STIR sequence before (A) and 2 weeks after (B) treatment with a full dose of an NSAID. Near-complete resolution of active inflammation (arrows) is seen after 2 weeks.

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a substantial proportion of patients (35%) in the naproxen alone arm. Complete absence of active inflammatory lesions in the sacroiliac joints was observed at week 28 in 5.9% of the patients treated with naproxen (compared with 27.6% in the naproxen plus infliximab group), whereas no patients in this arm (18.1% in the combined arm) were free of inflammation in both spine and sacroiliac joints.14 However, because this study had no placebo arm, whether the resolution of the inflammation in the sacroiliac joints was a result of the naproxen use or the natural course of the disease is unclear. These data indicate clearly that, although NSAIDs might have some influence on active inflammation in the axial skeleton, inflammation (in axial skeleton or systemic) might persist even when there is absence or good control of symptoms. Whether this asymptomatic inflammation, indicated by elevated serum CRP or osteitis on MRI, has clinical relevance is currently unclear. Current treatment recommendations rely mainly on symptoms,1,2 and therefore no treatment modification is generally recommended for patients who respond well to NSAIDs but still have some signs of systemic or local inflammation.
INFLUENCE OF NSAIDS ON RADIOGRAPHIC SPINAL PROGRESSION IN AXSPA/AS

The high efficacy of NSAIDs in reducing clinical symptoms, and to some extent reducing signs of systemic inflammation (CRP), raises the question whether NSAIDs are only symptomatically effective or whether they might have an additional effect on the long-term outcome of axSpA/AS. Radiographic spinal progression, which is mostly related to the process of new bone formation, or the development of syndesmophytes leading to the bony ankylosis of the spine (Fig. 2), seems to be an important determinant of long-term outcome in axSpA. Currently available data indicate a clear (although nonlinear) association

Fig. 2. Radiographs of the cervical spine in a lateral view of a patient with AS performed 2 years apart, showing a very quick radiographic progression with development of several new bridging syndesmophytes (arrows) over 2 years.

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between radiographic damage in the spine and impaired spinal mobility20,21 and reduction of physical function.21,22 Therefore, retardation of radiographic spinal progression represents a logical treatment target in axSpA. Years ago, Boersma23 showed that continuous use of phenylbutazone was associated with retardation of spinal ossification in AS. In a more recent study by Wanders and colleagues,24 continuous (daily) use of NSAIDs (all starting with celecoxib but changing to other NSAIDs in cases of clinical inefficacy or intolerance) was also associated with an inhibition of radiographic progression in the spine over 2 years compared with on-demand use. The most recent data from the German Spondyloarthritis Inception Cohort supports these findings. High NSAID intake (NSAID intake index !50) over 2 years was associated with lower radiographic spinal progression compared with low NSAID intake (NSAID intake index <50) in patients with AS. In nr-axSpA, no significant differences in radiographic progression were seen between patients with high and low NSAID intake, which was most likely related to the low level of spinal damage in general in this group. Retardation of radiographic spinal progression during NSAID therapy was nearly exclusively seen in patients with risk factors for this progression (presence of syndesmophytes at baseline and elevated CRP). Radiographic spinal progression rate as assessed by a mean worsening of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS)25 over 2 years was 4.36 4.53 in patients with low NSAID intake versus 0.14 1.80 in those with high intake (P 5 .02).26 The recent post hoc analysis27 of the data from the study by Wanders and colleagues confirmed these findings. An inhibitory effect of continuous NSAID use was observed in patients with elevated acute-phase reactants (CRP or erythrocyte sedimentation rate [ESR]) only. For instance, in the subgroup of patients with elevated time-averaged CRP, the mean mSASSS progression over 2 years was 1.7 2.8 in those with on-demand NSAID intake versus 0.2 1.6 in those with continuous NSAID intake (P 5 .003), whereas in the subgroup with normal CRP, no difference in a mean mSASSS change was seen (0.8 1.1 vs 0.9 1.8, respectively, for the on-demand and continuous arms; P 5 .62). Similarly, a difference between on-demand and continuous arms in terms of percentages of patients who showed radiographic spinal progression (defined as an mSASSS worsening by at least 2 units over 2 years) was seen exclusively in the subgroups with elevated acute-phase reactants (CRP or ESR); in the patients with elevated CRP, the percentages of progressors were 38% versus 13%, respectively (P 5 .011).27 Defining the patient type that would benefit from continuous treatment at most is necessary for the development of individualized treatment strategies for axSpA. However, clinical indications for NSAID therapy defined by the level of pain and stiffness currently have clear priority over radiographic indications. Practically, this means that the need for NSAID treatment should be justified based on symptom levels, whereas risk factors for radiographic progression (such as syndesmophytes or elevated acute-phase reactants) play a secondary role. The mechanism of NSAID inhibition of radiographic spinal progression in AS is not fully understood. However, this effect clearly cannot be attributable only to the anti-inflammatory properties of NSAIDs, because the most potent anti-inflammatory drugs currently available for the treatment of AS (TNF-a blockers) have failed to slow radiographic spinal progression over 2 years in clinical trials.2830 Most likely, NSAIDs inhibit new bone formation in the spine (morphologic substrate of syndesmophytes and ankylosis) through preventing prostaglandin E2dependent replication and differentiation of osteoblasts31,32 and inhibiting prostaglandin-dependent angiogenesis, which is required for osteogenesis.33 Because retardation of new bone formation is related to COX-2 inhibition, no substantial differences are expected between various NSAIDs, because in therapeutic

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concentrations, all NSAIDs, independent of their COX selectivity, inhibit COX-2 to nearly the same extent.34 Given the good anti-inflammatory capacity of TNF blockers in AS but their failure to stop new bone formation, a trial combining a TNF blocker and an NSAID would be of interest to determine whether this combination could inhibit new bone formation, in addition to suppressing inflammation and improving signs and symptoms. This clinical question is also important to answer because it will determine whether patients at risk for radiographic progression should be advised to continue the use of NSAIDs when they are no longer necessary for symptom modification.

SAFETY OF NSAIDS AND RISK/BENEFIT ESTIMATION OF NSAID THERAPY IN SPA

Serious safety concerns are always raised when long-term NSAID treatment is discussed. Several safety aspects are related to NSAID treatment, such as gastrointestinal, cardiovascular, renal, hepatic, and allergic reactions. The most common and clinically relevant are the first 2, which are discussed further. Gastrointestinal toxicity is a well-known adverse effect during NSAID treatment, which is related mainly to inhibition of prostaglandin synthesis in the gastric mucosa. The most important aspect of the gastrointestinal toxicity is gastroduodenal ulceration and development of ulcer complications, such as gastrointestinal bleeding, perforation, and gastric outlet obstruction. Three large trials comparing COX-2selective with nonselective NSAIDs showed a rate of serious gastrointestinal events (symptomatic gastroduodenal ulcers and ulcer complications) of 0.67 to 1.85 per 100 patient-years for COX-2selective inhibitors and 0.97 to 3.21 per 100 patient years for nonselective NSAIDs.3537 At the same time, the rate of complications only (without symptomatic ulcers) was approximately 1 or less per 100 patient years for both COX-2selective and nonselective NSAIDs.3537 The risk of gastrointestinal adverse events is strongly dependent on the presence of risk factors, and therefore it can be recommended that patients be stratified according to gastrointestinal risk before NSAIDs are administered, and overall risk be reevaluated in case of a risk profile change. The following risk factors should be taken into account: previous gastrointestinal events, especially if complicated; age; concomitant use of anticoagulants, corticosteroids, and other NSAIDs, including low-dose aspirin and high-dose NSAID therapy; chronic debilitating disorders, especially cardiovascular disease; and Helicobacter pylori infection (a potential advantage exists to testing for H pylori infection and eradicating the infection if positive in patients requiring long-term NSAID therapy, especially those with a history of ulcers).38 The American College of Gastroenterology recently recommended the following patient stratification system according to risk of NSAID gastrointestinal toxicity38: 1. High risk a. History of a previously complicated ulcer, especially recent b. Multiple (>2) risk factors 2. Moderate risk a. Age >65 years b. High-dose NSAID therapy c. A previous history of uncomplicated ulcer d. Concurrent use of aspirin (including low-dose), corticosteroids, or anticoagulants 3. Low risk a. No risk factors

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Prevention of NSAID gastrointestinal toxicity includes use of gastroprotectors (proton pump inhibitors or misoprostol), use of selective COX-2 inhibitors instead of nonselective ones, and eradication of H pylori infection.38,39 To define an appropriate method of prevention, cardiovascular risk should be also taken into account. Current evidence suggests that both selective COX-2 inhibitors (coxibs) and nonselective NSAIDs, with the possible exception of full-dose naproxen, increase cardiovascular risk. This effect was clearly shown in a meta-analysis of randomized trials by Kearney and colleagues40 and confirmed later in a large population-based study from Denmark41 and the most recent meta-analysis by Trelle and colleagues.42 Furthermore, no difference seems to exist between coxibs (at least for those that are currently marketed, celecoxib and etoricoxib) and nonselective NSAIDs in their influence on cardiovascular risk.43,44 Obviously, the individual cardiovascular risk depends on numerous well-known traditional cardiovascular risk factors, such as smoking, diabetes, age, previous cardiovascular events, and NSAID dose used. Large clinical trials showed that rates of cardiovascular events were especially low in younger patients and those with low baseline cardiovascular risk (less than 1 event per 100 patient years).44,45 This finding is especially relevant for the current discussion, because SpA is a disease of young people starting normally in the third decade of life. As suggested by the American College of Gastroenterology, nonselective NSAIDs can be administered safely in patients with low cardiovascular risk (who do not take low-dose aspirin) and low gastrointestinal risk. A selective COX-2 inhibitor or a combination of a nonselective NSAID with a gastroprotector should be used in patients with moderate gastrointestinal risk, and an alternative therapy or, if not possible, the combination of a coxib and a gastroprotector should be considered in patients with high gastrointestinal risk.38 In patients with high cardiovascular risk (defined as a need for low-dose aspirin intake) and low or moderate gastrointestinal risk, the combination of naproxen with gastroprotective agents is recommended. If both cardiovascular and gastrointestinal risks are high, NSAIDs should be generally avoided and an alternative therapy should be considered.38 Most of the data concerning NSAID safety originate from clinical trials including patients with rheumatoid arthritis or osteoarthritis. Nonetheless, in the 3 available long-term NSAID trials in patients with AS (!1 year), no toxicity signals different from those discussed earlier were reported and the incidences of adverse events or discontinuations from adverse events did not differ significantly within treatment groups or between treatment and placebo groups.8,9,24 In the recent observational study from Norway, frequent use of NSAIDs in AS was clearly associated with decreased overall mortality.46 These data require confirmation, but it could be speculated that anti-inflammatory effects of NSAIDs, reflected by the decrease in the serum CRP level, might counterbalance the increase of the cardiovascular risk in AS related to systemic inflammation and the NSAID treatment itself.47 Thus, taking into account the relative young age and the low comorbidity in patients with AS, serious adverse events can be expected to occur in approximately 1% or fewer per year if patients are treated with a full dose of an NSAID. An NSAID should be selected according to its expected benefit in a given patient and according to the patients risk profile to help achieve a favorable benefit/risk ratio.47
SUMMARY

NSAIDs are highly effective in reducing symptoms of axSpA, including AS, and therefore considered a first-line therapy in this disease. NSAIDs might have an impact on

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radiographic spinal progression in AS if administered continuously. The greatest effect on radiographic progression is expected in patients with syndesmophytes who have an elevated CRP. However, the primary goal of treatment in patients with AS should be to eliminate symptoms, whereas retardation of radiographic progression represents a secondary goal of treatment, although relevant for the long-term outcome. Careful assessment of the cardiovascular, gastrointestinal, renal, and hepatic risk profile is required before administering an NSAID, especially if a long-term and continuous treatment is expected. Regular reassessment of the risks in patients treated with continuous NSAIDs is recommended.
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14. Sieper J, Lenaerts J, Wollenhaupt J, et al. Double-blind, placebo-controlled, 28-week trial of efficacy and safety of infliximab plus naproxen vs naproxen alone in patients with early, active axial spondyloarthritis treated with a submaximal dose of NSAIDs: preliminary results of INFAST Part I. Ann Rheum Dis 2012; 71(Suppl 3):247. 15. Dougados M, Simon P, Braun J, et al. ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis. Ann Rheum Dis 2011;70(2):24951. 16. Poddubnyy DA, Rudwaleit M, Listing J, et al. Comparison of a high sensitivity and standard C reactive protein measurement in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Ann Rheum Dis 2010;69(7):133841. 17. Poddubnyy D, Rudwaleit M, Haibel H, et al. Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Ann Rheum Dis 2011;70(8):136974. 18. Poddubnyy D, Haibel H, Listing J, et al. Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum 2012;64(5):138898. 19. Jarrett SJ, Sivera F, Cawkwell LS, et al. MRI and clinical findings in patients with ankylosing spondylitis eligible for anti-tumour necrosis factor therapy after a short course of etoricoxib. Ann Rheum Dis 2009;68(9):14669. 20. Wanders A, Landewe R, Dougados M, et al. Association between radiographic damage of the spine and spinal mobility for individual patients with ankylosing spondylitis: can assessment of spinal mobility be a proxy for radiographic evaluation? Ann Rheum Dis 2005;64(7):98894. 21. Machado P, Landewe R, Braun J, et al. Both structural damage and inflammation of the spine contribute to impairment of spinal mobility in patients with ankylosing spondylitis. Ann Rheum Dis 2010;69(8):146570. 22. Landewe R, Dougados M, Mielants H, et al. Physical function in ankylosing spondylitis is independently determined by both disease activity and radiographic damage of the spine. Ann Rheum Dis 2009;68(6):8637. 23. Boersma JW. Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone. Scand J Rheumatol 1976;5(1):604. 24. Wanders A, Heijde D, Landewe R, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum 2005;52(6):175665. 25. Creemers MC, Franssen MJ, vant Hof MA, et al. Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis 2005;64(1):1279. 26. Poddubnyy D, Rudwaleit M, Haibel H, et al. Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German spondyloarthritis inception cohort. Ann Rheum Dis 2012;71(10):161622. 27. Kroon F, Landewe R, Dougados M, et al. Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis 2012;71(10):16239. 28. van der Heijde D, Landewe R, Einstein S, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum 2008;58(5):132431. 29. van der Heijde D, Landewe R, Baraliakos X, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 2008;58(10):306370.

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